Small molecule inhibitor of FOXA1 and FOXA2 for the treatment of FOXA1 / FOXA2-dependent cancers or other diseases

Abstract

The present invention relates to new inhibitors of the transcription factor FOXA1 and / or FOXA2 for use in a method of treatment of cancer or other FOXA1 / FOXA2-dependent diseases.

Description

[0001] “Small molecule inhibitor of F0XA1 and F0XA2 for the treatment of F0XA1 / F0XA2-dependent cancers or other diseases”

[0002] TECHNICAL FIELD OF THE INVENTION

[0003] The present invention relates to new inhibitors of the transcription factor F0XA1 and / or F0XA2 for use in a method of treatment of cancer or other FOXA1 / FOXA2-dependent diseases.

[0004] BACKGROUND OF THE INVENTION

[0005] F0XA1 and F0XA2 are two pioneer transcription factors that share 90% of amino acid sequence in their forkhead DNA binding domain. In cancer, both transcription factors are selectively required for the growth of cancer cells related to distinct cancer types (https: / / depmap.org). Most notably, FOXA1 is required to sustain the growth of breast and prostate cancer cells, while FOXA2 is more selectively required for cancer growth of adenocarcinoma of the stomach, neuroendocrine & small cell lung cancer, and hepatocellular carcinoma. In addition, more recent evidence suggests a critical involvement of FOXA2 for more advanced lineage-plasticity prostate cancers of different subtypes.

[0006] Accordingly, FOXA1 and FOXA2 are interesting drug targets because cancer cells depend on their function for tumor growth. Nevertheless, there is a need of small molecules that stereoselectively and site-specifically inhibit such drug targets.

[0007] SUMMARY OF THE INVENTION

[0008] The inventors identified a new class of potent inhibitors of the transcription factor FOXA1 and / or FOXA2 as also shown in the examples and experimental sections of the present description.

[0009] A first object of the present invention is a compound having formula T:

[0010]

[0011] Formula T

[0012] wherein:

[0013] R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are selected independently of each other from:

[0014] H, OH, CH3, CH2CH3, OCH2CH3, COOH or an amide or an carbonyl group or a sulfamide or a halogen atom selected from: Cl, F, Br, I or an alkyl group selected from: methyl group or ethyl-methyl group, isobutyl or tert-butyl;

[0015] wherein Xi, X2, X3, X4, X5, XG, X7, Xs, X9, X10 are selected independently of each other from O, N, C and S, wherein n is between 0 and 3, for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases.

[0016] A second object of the present invention is any of the compounds herein disclosed for use as inhibitors of the transcription factor F0XA1 and / or F0XA2 in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases, in particular for use in the treatment of cancer selected from breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer and hepatocellular carcinoma.

[0017] A third object of the present invention is a pharmaceutical composition comprising any of the compounds herein disclosed for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases. BRIEF DESCRIPTION OF THE FIGURES

[0018] Figure 1. Small molecules and derivatives emerging from virtual drug screening. (A, B) Structures of small molecules using the crystal structure of the FOXA2 forkhead domain as bait. Panel A (Latin characters) and B (Greek characters) depict compounds from two different libraries.

[0019] Figure 2. FOXA1 / 2-related Luciferase Assays testing activity of compounds depicted in Fig. 1. (A) Percent reduction of luciferase reporter assay activity induced by FOXA1 using the indicated compounds at 100 micromolar for 24 hours in 293T cells. (B) Different concentrations were tested for compound T in the corresponding assay. (C) A different set of compounds was tested in the corresponding assay at 100 micromolar for 24 hours in 293T cells. (D, E) Compound S, T, U tested at various concentrations using the same assay related to FOXA1 (D) and FOXA2 (E). (F) Percentage of luciferase reduction of compound T tested at 100 micromolar against different FOX-family proteins. Statistical significance as indicated by asterisk: * p<0.05, **p<0.01, ***<0.001, student t-test

[0020] Figure 3. Biophysical testing of compound T with the recombinant forkhead domain of FOXA1. (A-E) Representative surface plasmon resonance (SPR) data for indicated compounds (see Fig. 1) using the immobilized FOXA1 forkhead domain. Compound T displays a dissociation constant (Kd) of 100 micromolars. (F) Compound T reduces the melting temperature of the forkhead domain in Differential scanning fluorimetry (DSF). (G) Results of BLI experiment for the binding of FoxA1 forkhead domain to a DNA dsOligo with and without preincubation with T at a 100 micromolar concentration. (H) Markus structure generalizing the properties of compound T and putative new derivates enabling forkhead domain binding to FOXA1 / 2. Ri, R2, R3, R4, Rs, Re, R7, Rs, Rg, R are selected independently of each other from: H, OH, CH3, CH2CH3, OCH2CH3, COOH or an amide or an carbonyl group or a sulfamide or a halogen atom selected from: Cl, F, Br, I or an alkyl group selected from: methyl group or ethyl-methyl group, isobutyl or tert-butyl, also X are selected independently of each other and can be O, N, C and S for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases. (I) Results of the docking claculations. On the right, superposition between the best docking solution and the FoxA1-DNA complex (pdb code TVOX), in the middle best docking solution for T-FoxA1 complex, on the right T projected on neighboring amino acids. Figure 4. Effects of compound T on FOXA1 / 2 binding on chromatin determined by ChlP-seq. (A) Effect of 100 micromolar of compound T on global FOXA1 chromatin occupancy in LNCaP cells. (B) Corresponding differences in related to the cooccurrence of distinct motifs. (C) Scattered plot showing predominant co-localization of FOXA1 and FOXA2 at the chromatin in PC3 cells. Grey code of the peak regions indicates AT content. (D) Corresponding effect of 100 micromolar of T on global FOXA1 and FOXA2 chromatin occupancy in PC3 cells. (E, F) Corresponding differences in related to the cooccurrence of distinct motifs for FOXA1 (E) and FOXA2 (F).

[0021] Figure 5. Effect of compound T on FOXA1 / 2-dependent molecular changes. (A) Immunoblot of the indicated proteins of LNCaP cells treated with 50 and 100 micromolar of compound T in the presence and absence of dihydrotestosterone (DHT). (B) Immunoblot of the indicated proteins of PC3 cells with either knockdown of FOXA1, FOXA2 and double knockdown of both FOXA1 and FOXA2 using a short-hairpin RNA. (C) Immunoblot of the indicated proteins of PC3 cells treated with different concentrations of compound T for 1 and 3 days, respectively. (D) Immunoblot of the indicated proteins of H660 cells with either knockdown of FOXA1, FOXA2 and double knockdown of both FOXA1 and FOXA2 using a short-hairpin RNA. (E) Immunoblot of the indicated proteins of H660 cells treated with different concentrations of compound T for 1 and 3 days, respectively.

[0022] Figure 6. Differential killing of compound T in FOXA1 / 2-positive versus negative cells. (A, B) Immunoblotting for the indicated proteins in the indicated cell lines. (C) Corresponding growth inhibition curves using various concentrations of compound T. (D) The IC50 (half-maximal inhibitory concentration) value required to inhibit cell proliferation by 50% in the indicated cell lines.

[0023] Figure 7. Small molecules derivates emerging T compound. Structures of small molecule derivatives dT1-dT27.

[0024] Figure 8. FOXA1 / 2-related Luciferase Assays testing activity of compounds depicted in Fig. 7. (A) Percent reduction of luciferase reporter assay activity induced by FOXA1 using the indicated compounds at 20 micromolar for 24 hours in 293T cells. (B) Corresponding assay using the same compounds at 70 micromolar. (C) Different concentrations were tested for compound dT3, dT4, dT5, and T in the same assay. Figure 9. Comparison between the results of biophysical testing of dT1-27 with the recombinant forkhead domain of FOXA1 and the physicochemical properties of the molecules. (A) Ko-values of T and derivatives tested for binding by SPR and the indicated recombinant forkhead domains. (B) The partition coefficient between n-octanol andwater (clogP, x-axis) plotted against the dissociation constants (KD, y-axis) of T and derivates dT1-27 (Fig. 7). (C) The SPR sensogram of dT15 with a KD of around 1 micromolar. While dT3 and dT4 display clearly an enhanced activity, dT15 may not be active because of its higher hydrophilicity that may prevent the penetrance of cell membranes (see Fig. 7).

[0025] Figure 10. Effect of T derivates on FOXA1 -dependent transcription factors and cell proliferation in LNCaP prostate cancer and MCF-7 breast cancer cells. (A) Reduction of protein abundance of AR-related transcription factors is enhanced in the more active T-derivates dT3 and dT4. (B) Corresponding reduction of protein abundance of estrogen receptor alpha (ER)-related transcription factors. (C) Reduction in proliferation of T derivates showing dT3 and dT4 but not dT2 and dT15 display anti-proliferative effects at low micromolar concentrations in LNCaP and MCF-7 cells.

[0026] Figure 11. Anti-tumor activity of dT3 and dT4 in vivo in a PC3-derived xenograft model. (A) Growth kinetics of PC3 xenograft tumors treated three times per week with intraperitoneal injection of either vehicle (corn oil, CTR) and 12.5 mg / kg dT3 as indicated. (B) Corresponding assay using 25mg / kg of dT4. N = 5 animals in each experimental group. Data are represented as mean ± SEM. DETAILED DESCRIPTION OF THE INVENTION

[0027] The present invention relates to compounds having formula T:

[0028]

[0029] Formula T

[0030] wherein:

[0031] R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are selected independently of each other from:

[0032] H, OH, CH3, CH2CH3, OCH2CH3, COOH or an amide or an carbonyl group or a sulfamide or a halogen atom selected from: Cl, F, Br, I or an alkyl group selected from: methyl group or ethyl-methyl group, isobutyl or tert-butyl;

[0033] wherein Xi, X2, X3, X4, X5, XG, X7, Xs, X9, X10 are selected independently of each other from O, N, C and S;

[0034] wherein n is between 0 and 3, preferably n is 0, for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases.

[0035] The present invention relates to the use of such compounds as inhhibitors of the transcription factor FOXA1 and / or FOXA2, in particular human Hepatocyte nuclear factor 3-alpha (FOXA1, UNIPROT entry P55317) and / or Hepatocyte nuclear factor 3-beta (F0XA2, UNIPROT entry Q9Y261), for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases, wherein said cancer is selected from breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer and hepatocellular carcinoma.

[0036] The present invention relates to the use of such compounds as in a method of treatment of a cancer selected from breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer and hepatocellular carcinoma.

[0037] In one embodiment in the formula T, R5 is CH3, or a H or a halogen.

[0038] In one embodiment in the formula T, R1 is H, or a halogen, or a OCH2CH3 or a COOH. In one embodiment in the formula T R2 is H, or CH2CH3 or a halogen, or OH or COOH. In one embodiment in the formula T, in R3 is a halogen, or COOH, or H, or OCH2CH3, CH3, OH.

[0039] In one embodiment in the formula T, R4is H, or CH3, a halogen.

[0040] In one embodiment in the formula T, Re is a H, or COOH, or a halogen, or an amide, or a sulfamide, or a carbonyl group.

[0041] In one embodiment in the formula T, R? is H, or a carbonyl group, or a halogen, or CH3, or COOH.

[0042] In one embodiment in the formula T, Rs is H, or a halogen.

[0043] In one embodiment in the formula T, Rg is H, or a carbonyl group, or a halogen, or CH3, or COOH.

[0044] In one preferred embodiment in the formula T, R10 is COOH, or H, or a halogen, or an amide, or a sulfamide, or a carbonyl group, or an alkyl group.

[0045] In one preferred embodiment in the formula T, R5, R1, R2 and / or R3 is a COOH or a halogen, R10 and / or Re is COOH, H, a halogen ora carbonyl group.

[0046] In one preferred embodiment in the formula T, R4, R7, Rs and / or Rg is H, a halogen, OCH2CH3 or a COOH.

[0047] In one preferred embodiment in the formula T, R10 is selected from OH, CH3, CH2CH3, OCH2CH3, COOH, an amide, carbonyl group, a halogen, an alkyl group and Re, R7, Rs, Rg is H. In one preferred embodiment halogen is Cl. In one more preferred embodiment in the formula T, R5, R1, R2, R3, R10 and / or R6 is COOH.

[0048] In one preferred embodiment in the formula T, Xi, X2, X3, X4, X5, XG, X7, XS, X9, XIO are all C atoms.

[0049] In one preferred embodiment in the formula T, Xi, X2, X3, X4, X5, X6, X7, Xs, X9, Xio are all C atoms and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is COOH.

[0050] In one preferred embodiment in the formula T, Xi, X2, X3, X4, X5, X6, X7, Xs, X9, Xio are all C atoms and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is OCH2CH3. In one more preferred embodiment in the formula T, Xi, X2, X3, X4, X5, XG, X7, XS, X9, XIO are all C atoms and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is COOH and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is OCH2CH3.

[0051] In one more preferred embodiment in the formula T, Xi, X2, X3, X4, X5, X6, X7, Xs, X9, Xio are all C atoms and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is COOH and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is OCH2CH3.

[0052] In one more preferred embodiment in the formula T, Xi, X2, X3, X4, Xs, Xs, X7, Xs, X9, Xio are all C atoms and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is COOH or OCH2CH3 and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is a Halogen, preferably Cl and n is 0.

[0053] In one more preferred embodiment in the formula T, Xi, X2, X3, X4, X5, X6, X7, Xs, X9, Xio are all C atoms and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is COOH or OCH2CH3 and at least one from RI, R2, R3, R4, Rs, Rs, R7, Rs, R9, or R10 is a Halogen, preferably Cl and n is 0. The atoms in Xi, X2, X3, X4, X5, XG, X7, XS, X9 X10 may be C or N in any positions independently of each other.

[0054] In one preferred embodiment the compound having the formula T:

[0055]

[0056] Formula T

[0057] where in:

[0058] n is 0;

[0059] Xi, X2, X3, X4, X5, X6, X7, X8, X9, and X10 is C;

[0060] R4 or Rsis COOH;

[0061] RI, R2and R3 is H;

[0062] Rs, R7, Rs, R9, and R10 are selected independently of each other from:

[0063] H, CH3, or a halogen atom selected from: Cl, F, Br, I; In one preferred embodiment the compound having the formula T:

[0064]

[0065] Formula T

[0066] where in:

[0067] n is 1;

[0068] Xi, X2, X3, X4, X5, X6, X7, X8, X9, and X10 is C;

[0069] R4or Rs is COOH;

[0070] RI, R2and R3is H;

[0071] Re, R7, Rs, R9, and R10 are selected independently of each other from: H, CH3, or a halogen atom selected from: Cl, F, Br, I;

[0072] In one preferred embodiment the compound having the formula T:

[0073]

[0074] Formula T

[0075] where in:

[0076] n is 0;

[0077] Xi, X2, X3, X4, X5, X6, X7, X8, X9, and X10 is C; R4 or Rs is COOH;

[0078] RI, R2, Rs, Re, R7, Rs, R9, and R10 are selected independently of each other from:

[0079] H, CH3, or Cl.

[0080] In one embodiment the compound of the invention is selected from one of the following compounds:

[0081]

[0082]

[0083] In one preferred embodiment the compound of the invention is selected from one of the

[0084]

[0085] In one preferred embodiment the compound of the invention is selected from one of the following compounds:

[0086]

[0087]

[0088] In one preferred embodiment the compound of the invention is selected from one of the following compounds:

[0089]

[0090] In one preferred embodiment the compound of the invention is selected from one of the following compounds:

[0091]

[0092]

[0093] In one preferred embodiment the compound of the invention is selected from one of the following compounds:

[0094]

[0095] The present invention relates also to any of the compounds herein disclosed for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases, in particular in the treatment of breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer or hepatocellular carcinoma.

[0096] The present invention relates also to a process for manufacturing the compounds herein disclosed comprising the following steps:

[0097]

[0098] where in:

[0099] R1, R2, R3, R4, R5, R6, R7, R8, R9, R10 are selected independently of each other from:

[0100] H, OH, CH3, CH2CH3, OCH2CH3, COOH or an amide or an carbonyl group or a sulfamide or a halogen atom selected from: Cl, F, Br, I or an alkyl group selected from: methyl group or ethyl-methyl group, isobutyl or tert-butyl.

[0101] In an alternative embodiment of the compound iv in the process for manufacturing the compounds herein disclosed, has a (CH2)n group, preferably with n values between 0 and 3, wherein said (CH2)n group is bound both to nitrogen of the sulfonamide group and the aromatic ring, wherein said aromatic ring can have different substituents Re, R7, Rs, Rg, R - Preferably the compounds of the present invention are used in the treatment of a cancer selected from breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer and hepatocellular carcinoma, more preferably in the treatment of a prostate cancer.

[0102] Preferably the compounds of the present invention are used in combination with hormonal therapy, targeted therapies, chemotherapy, radiotherapy, immunotherapy, or any new type of therapy that may emerge in the future. For prostate cancer, combinations may include thus established therapeutic modalities such as androgen deprivation therapy (e.g., LHRH agonist or antagonists), androgen signaling inhibitors (e.g., enzalutamide, apalutamide, darolutamide, abiraterone), chemotherapy (e.g., docetaxel or carboplatin), radioligand therapy (e.g., 177-Lutecium-PSMA-617), PARP- inhibitors (e.g., olaparib), or immune checkpoint inhibitors (e.g., pembrolizumab, dostarlimab). In breast cancer, combinations my include but are not limited to established therapeutic modalities such as hormonal therapy, such as selective estrogen receptor modulators (SERMs, e.g., tamoxifen), aromatase inhibitors (e.g., anastrozole), selective estrogen receptor degraders (SERDs, e.g., fulvestrant), targeted therapies such as CDK4 / 6 inhibitors (e.g., palbociclib), PARP-inhibitors (e.g., olaparib) or anti-HER2 targerting small molecules or antibodies (e.g., trastuzumab, trastuzumab emtansine, trastuzumab deruxtecan), chemotherapy (e.g., capecitabine, carboplatin, epirubicin, vinorelbine, cyclophosphamide, docetaxel, gemcitabine, doxorubicin), or immune checkpoint inhibitors (e.g., pembrolizumab). In analogy, FOXA1 / 2 inhibitors may be combined with the current or future standard care in adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer and hepatocellular carcinoma.

[0103] It’s also herein disclosed a pharmaceutical composition comprising one or more of any of the compounds herein disclosed for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases, in particular in the treatment of breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer or hepatocellular carcinoma.

[0104] The herein described pharmaceutical compositions could include one or more excipients and / or diluents, the person skilled in the art could select such excipients and / or diluents suitable depending upon the selected formulation.

[0105] Moreover, each one of these forms can be of conventional type or with modified release (for example with immediate, rapid, prolonged or delayed release). Under the expression "pharmaceutical forms with modified release (or not conventional forms)" the dosage forms are herein meant, therefor the profile for releasing (and then absorbing) the active ingredient depends upon both the chemical and physical features of such ingredient and upon the characteristic technology of the formulation. The factor determining the absorption profile is the speed of releasing the active ingredient from the pharmaceutical form.

[0106] Under the expression "agent which modifies the release" of an active ingredient in the organism a compound is herein meant capable of modifying the speed or the dissolution site and, consequently, the absorption of an active ingredient by the tissues and the body fluids, therewith it comes in contact after administration.

[0107] Examples of various classes of such agents are: disintegrating agents (compounds which facilitate the disintegration of solid pharmaceutical forms, by increasing the surface in contact with the biological fluids and thus by increasing the speed for releasing and absorbing the active ingredient); surfactants (compounds which are added to the solid preparations to increase the product wettability and then the disintegration thereof); polymers (compounds which modify the time or the site for releasing the active ingredient, for example in preparations with prolonged release or gastro-resistant preparations).

[0108] All these above-listed agents can be used for mono-or multi-layer tablets, swallable, chewable, buccal or sublingual tablets or granules, for capsules or sachets.

[0109] Under the term "excipient", reference is made to conventional excipients, that is compounds that are inert towards the active ingredient and the pharmaceutical form. Examples of different classes of these ingredients are: diluents (compounds added when the mass of the active ingredient is not sufficient for preparing the composition); lubricants (preventing the power from adhering to the mechanical parts during the manufacturing process); aggregating agents (compounds which increase the cohesion of powders); dyes (used to improve the presentation of some pharmaceutical dosage forms, for example capsules, or to classify them based upon the therapeutical category to which they belong or to distinguish them from other similar products); sweeteners or flavourings (added to improve the organoleptic features of the products); or antioxidants-antimicrobials (used to prolong the product shelf life).

[0110] Examples of such diluting, aggregating or binding agents, lubricants, slippers, disaggregating agents, solubilizers and / or pH regulators are the following ones: light magnesium oxide, magnesium hydroxide, alginic acid, stearic acid, hydrogenated vegetable oils (palm, oleic or behenic), cocoa butter, cocoa paste, chitosan, yeast, sodium carboxymethylcellulose (CMC), pregelatinized corn starch. The most commonly used conventional excipients are the following ones: lactose, glucose, sucrose, mannite (or mannitol), kaolin, talc, bentonite, titanium dioxide, xylitol, maltitol, sorbitol, sucralose, acesulfame K, aspartame, neohesperidin, fructose, dextrose, maltose, "spraydried" malt, sodium aspartate, maltodextrin, sodium chloride, hydroxypropyl methylcellulose, erythritol, citrus extract, silica gel, vegetable fibres (such as pea fibre), flavours and aroma, such as for example mint flavour (peppermint, crispa, sweet), badiana anethole, vanilla, sage, grapefruit, peach, orange, lemon or lime, sodium glutamate an fish meal.

[0111] It’s also herein disclosed also a method of treatment a cancer or any other FOXA1 / FOXA2-dependent diseases, comprising a step of admistering one or more of the compounds herein disclosed to a patient suffering such disease.

[0112] The compounds of the invention

[0113] In any part of the present description and claims, the term comprising can be replaced by the term "consisting of".

[0114] Examples are reported herebelow having the purpose of illustrating better the methods disclosed in the present description, such examples are in no way to be considered a limitation of the preceding description and of the subsequent claims.

[0115] EXAMPLES EXAMPLE 1

[0116] Synthesis of 2-((4,5-dichloro-2-methylphenyl)sulfonamido)benzoic acid (T)

[0117]

[0118] 4,5-dichloro-2-methylbenzenesulfonyl chloride (2)

[0119] To a mixture of CISO3H (12.5 eq.) and SOCI2 (1 eq.) stirred at 0 °C was slowly added 1,2-dichloro-4-methylbenzene (1) (5 eq.) and stirred for 1 h. Then stirring was continued at room temperature for 18 h. The reaction mixture was poured into ice. The solid precipitated was filtered, washed with water and dried to give the title compound.

[0120] General synthetic pathway synthetic pathway used above is also disclosed in Bluke, Z., Paass, E., Sladek, M., Abel, U., & Kauss, V. (2015). Synthesis of 3,4-dihydro-2H-1,2-benzothiazine-3-carboxylic acid 1,1 -dioxides and their evaluation as ligands for NMDA receptor glycine binding site. Journal of Enzyme Inhibition and Medicinal Chemistry, 31(4), 664-673. https: / / doi. org / 10.3109 / 14756366.2015.1057722 herein incorporated by reference

[0121] 2-((4,5-dichloro-2-methylphenyl)sulfonamido)benzoic acid (T)

[0122] A solution of 2-aminobenzoic acid (3) (1 eq.) and Na2CO3 (2.4 eq.) in H2O (1.5 mL / mmol) was heated to 60°C. 4,5-dichloro-2-methylbenzenesulfonyl chloride (2) (1.2 eq.) was added, and the resulting suspension was stirred for 7 h. The reaction mixture was cooled to room temperature, 6 M HCI (aq) (0.5 mL / mmol) added slowly, and the resulting suspension stirred overnight. The precipitate was collected by vacuum filtration, washed with water, and dried in vacuo to give a crude solid. The material was further purified by semi-preparative HPLC (C18) eluting with a gradient from 5-95% MeCN in H2O buffered with 0.5% formic acid to give a white powder.

[0123] General synthetic pathway used for the synthesis of the compound disclosed above is also disclosed in Anthranilic amide and imidazobenzothiadiazole compounds disrupt Mycobacterium tuberculosis membrane potential Jake Smith, a Heather Wescott, a Julie Early, a Steven Mullen, a Junitta Guzman, a Joshua Odingo, Jason Lamarb and Tanya Parish https: / / d oi. orq / 10.1039 / C9M D00088G herein incoporated by reference. Example 2

[0124] Synthetic pathway for dT3. dT4. dT15

[0125]

[0126] 2-((3,4-dichlorophenyl)sulfonamido)benzoic acid (5)

[0127] The following procedure was described above and the same utilized for the synthesis of 2-((4,5-dichloro-2-methylphenyl)sulfonamido)benzoic acid (T). General procedure for dT3, dT4, dT15.

[0128] To a solution of the acid (5, 1.5 eq.) in dry THF (0.5 M) under inert atmosphere was added carbonyldiimidazole (CDI) (1.5 eq.). The mixture was stirred at room temperature for 10 minutes, and then the corresponding amine (1.0 eq.) was added. The reaction mixture was stirred overnight at 60 °C. Water was then added to quench the reaction, and the aqueous phase was extracted with Et2O (3x). The organic phases were combined, washed twice with a 1M NaOH solution, once with brine and then dried over MgSO4. The crude product was concentrated under reduce pressure and purified by flash chromatography on silica gel. The material was further purified by semi-preparative HPLC (C18) eluting with a gradient from 5-95% MeCN in H2O buffered with 0.5% formic acid to give a white powder. This general procedure is also disclosed in Silver-Promoted Synthesis of 5-(Pentafluorosulfanyl)methyl-2-oxazolines by Audrey Gilbert, Xavier Bertrand and Jean-François Paquin.

[0129] DOI: 10.1021 / acs.orglett.8b03170

[0130] EXPERIMENTAL DATA

[0131] Using a virtual drug screen on the published crystal structure of the forkhead domain of FOXA2 which shares 90% homology with FOXA1, the inventors identified and selected molecules and derivates thereof (Fig. 1A, B) and tested them in a luciferase reporter assay whereby multiple FOXA1 / 2 DNA motifs have been linked to a luciferase (PMID: 31243370) (Fig. 2.). Out of these, three compounds (termed S, U, and T) inhibited at higher micromolar concentration the luciferase signal induced by either FOXA1 or FOXA2 to a similar degree (Fig. 2A, B, D, E). That said, compound T emerged to be more potent than the other two. Finally, the inventors tested compound T for specificity towards inhibition of other FOX transcription factors and found that compound T suppresses similarly the luciferase signaling induced by FOXA3, FOXC1, and FOXO1A (Fig. 2F).

[0132] Subsequently, the inventors tested by SPR the binding of the compounds to the recombinant forkhead domain of FOXA1 produced in E. coli. While compound T bound to FOXA1 with a Kd value of 100 micromolar, the two compounds S and U with weaker activity displayed much weaker binding while inactive compound Q did not bind (Fig. 2A- E). Compound T further decreased the melting temperature of the FOXA1 forkhead domain in a DSF assay (Fig. 3F). Moreover, a BLI experiment revealed that preincubation of the FOXA1 forkhead domain with T at a 100 micromolar concentration prevents the forkhead domain from binding to a DNA dsOligo. Based on this information (Fig. 1-3), we delineate the Markus structure of the active compound T and putative derivates which may have similar or even more potent inhibitory activity (Fig. 3H). Finally, unsupervised molecular docking of compound T with the forkhead domain of FOXA1 identifies a best docking solution for compound binding (Fig. 31).

[0133] To further validate the in vivo activity of the compound T, the inventors performed ChIP sequencing on AR-positive LNCaP cells expressing FOXA1 and AR-negative PC3 prostate cancer cells expressing both FOXA1 and FOXA2. In LNCaP cells, compound T reduced the total chromatin occupancy of FOXA1 and more specifically FOXA1 at sites enriched for DNA binding motifs known to be important for androgen steroid hormone signaling (e.g., AR / HOXB13) (Fig. 4A, B). However, at sites enriched for motifs related to AP1 transcription factors (i.e., bZIP) peaks increased upon compound T exposure. In PC3 cells, compound T reduced both FOXA1 and FOXA2 peaks, most notably, at HOXB13 / AP1 sites that are critical for oncogenic signaling in this cell type, while increasing peaks at ETS transcription factor motifs (Fig. 4C-F). The data altogether shows that compound T reduces, in general, the binding of FOXA1 / 2 to the chromatin but also rewires FOXA1 / 2 distribution across the genome.

[0134] The inventors further investigated if compound T affects protein expression related to FOXA1 / 2 function in prostate cancer cells. In agreement with the function of FOXA1 enabling AR signaling in LNCaP cells, they found that compound T reduced FOXA1 expression and AR target genes (e.g., PSA, NKX3-1) in LNCaP cells (Fig. 5A). Moreover, they compared in PC3 cells, gene expression changes related the compound T with the double knockdown of FOXA1 / 2 and found that the two correlated with one another. Most notably, HOXB13 was reduced at the protein level in both PC3 cells with joint knockdown of FOXA1 and FOXA2 as well as treated with compound T (Fig. 5B, C). At last, they compared protein expression changes between double knockdown of FOXA1 / 2 with compound T in H660 cells. In both cases, the inventors observed downregulation of critical transcription factors related to neuroendocrine differentiation and oncogenesis, i.e., FOXA1, FOXA2, SOX2, ASCL1 (Fig. 5D, E).

[0135] The inventors tested if FOXA1 / 2 expressing prostate cancer cells (e.g., LNCaP, LAPC-4, PC3, H660, 22RV1) may be more susceptible to compound T compared to cells expressing very low levels (e.g. DU 145 prostate cancer cells, HS-5 fibroblasts, and 293T kidney cells, Fig. 6A, B). Indeed, the latter displayed a clearly reduced sensitivity to compound T and a higher IC 50 (Fig. 6C, D).

[0136] Subsequently, the inventors generated a new set of T-derivatives, labelled as dT1-27 (Fig.7) and tested them using the FOXA1 -driven luciferase assay mentioned above (Fig. 8A-C). Most notably, they identified with dT3, dT4, and dT5, three compounds with superior activity compared to the original T compound. They further determined the Ko-values of a subset of derivatives by SPR (dT1-27, Fig. 9A) and compared them to the octanol-water partition coefficient (Fig. 9B). Overall, more active compounds tended to be more lipophilic and have lower Ko-values while hydrophilic compounds have less activity regardless of their Ko-values. As expected, compounds with no measurable binding or no solubility (arbitrarily placed with a Ko-value of 1000 pM) did not show any activity in the luciferase assay. The best compound with respect to binding in this series (dT15) has an improved KD-value of around 1 pM in three independent SPR assays (Fig. 9C); while compound dT3 and dT4 with similar KD-value and increased lipophilicity as T showed also potent repression of the FOXA1 / 2-transactivation luciferase reporter mentioned (Fig. 8). Moreover, the derivatives dT3 and dT4 showed an increased reduction of FOXA1 / AR- related transcription factors in LNCaP prostate cancer cells and FOXA1 / estrogen receptor alpha (ER) transcription factors in MCF-7 breast cancer cells (Fig. 10 A, B) and a around 10-fold enhanced anti-proliferative effect in both cell lines as compared to the original T compound (Fig. 10C). Taken together, our new data indicates that modifications of the tool compound T can yield compounds wit increased potency and binding affinities that show distinct structure-activity patterns. Finally, the inventors tested the anti-tumor activity of the two best derivatives dT3 and dT4 in a PC3-derived xenograft tumor model. Based on a prior toxicity study, a dose of 12.5 mg / kg for dT3 and 25mg / kg for dT4 was established to have no substantial side-effects in immunocompromised NRG mice. Upon subcutaneous injection of PC3 cells into the flank of NRG mice, the inventors started to treat the tumors with a volume of 50 mm3with intraperitoneal injections of either vehicle control (corn oil), 12.5 mg / kg of dT3 or 25mg / kg of dT4, three times per week (Fig. 11 A, B). Both dT3 and dT4 injection impaired tumor growth in PC3 cells xenograft model (Fig. 11 A, B). MATERIAL AND METHODS

[0137] Virtual screening

[0138] Virtual screening calculations were conducted using the Schrodinger molecular modeling suite. Compound libraries were prepared with the LigPrep module, ensuring correct structures and protonation states. The virtual screening (VS) process was carried out with Glide employing progressively more sophisticated scoring functions: High Throughput Screening (HTS), Standard Precision (SP), and Extra Precision (XP). Finally, the top 20 molecules, ranked by XP GlideScore, were purchased from commercial vendors for experimental validation. The derivatives have been iteratively designed considering the results of docking calculations and of binding experiments.

[0139] Luciferase Reporter Assays

[0140] 293T cells were transiently transfected using JetPrime (Polyplus) with the pGL-6xFBS-Luc (as described in Adams et al., 2019, DOI: 10.1038 / s41586-019-1318-9) along with a pRL-CMV-Renilla (Renilla luciferase) internal control and the vector of interest: either pcw107 empty backbone (addgene #62511), pcw107-FOXA1 (in house cloned) or pcw107-FOXA2 (in house cloned) for each experiment. To optimize the assay the reporters were dose-response tested using different levels of pcw107-FOXA1 and pcw107-FOXA2. Compounds treatment was performed 2 hours after the transfection. Luminescence was measured 24h post-transfection using Dual-Glo Luciferase Assay System (Promega E2920) and response ratios were normalized to activity of pcw107-FOXA1 or pcw107-FOXA2 subtracting negative control activity of empty vector pcw107 (without exogenous FOXA1 or FOXA2). All results are means and standard deviations from experiments performed in biological triplicates and Firefly luciferase activity of individual wells was normalized against Renilla luciferase activity.

[0141] SPR

[0142] The binding interactions between the compounds with the FoxA1 or FoxA2 forkhead domain were studied using surface plasmon resonance (SPR). The protein was immobilized on a CM5 chip via amine coupling in acetate buffer at pH 4.5. A single-cycle kinetic method was used to inject six increasing concentrations of small molecule Q, ranging from 6.25 to 200 µM. Phosphate-buffered saline (PBS) containing 2% DMSO was employed as the running buffer to enhance solubility. Curve fitting was subsequently performed using Biacore Insight Evaluation Software (version 5.0.18).

[0143] DSF

[0144] Thermal stability of the protein samples was assessed using differential scanning fluorimetry (DSF) using the Protein Thermal Shift Dye Kit. The DSF experiments were performed in a total volume of 20 µL in 96-well PCR plates. Each well contained a final concentration of 2 µg of FoxA1 forkhead domain.

[0145] The reaction mixture was subjected to a thermal ramp from 25°C to 95°C at a rate of 0.05°C / sec using a qPCR machine. The experiments were performed using increasing concentration of T (from 3.12 to 200 µM). All the values are the average of the results obtained in four different wells. The Boltzmann-derived melting temperature Tm was plotted as function of the drug concentration. As negative control a single experiment considering a 100 µM concentration of compound Q was run. In this case we did not observe any perturbation of Tm.

[0146] BLI experiments

[0147] A biotinylated double-stranded oligonucleotide derived from a recently released cryo-EM structure, was dissolved in Sartorius Kinetics Buffer at a concentration of 2 µg / mL and immobilized onto Streptavidin (SA) Biosensors (https: / / doi.org / 10.1016 / j.molcel.2024.07.016). The binding interaction between the oligonucleotide and recombinant FoxA1 forkhead domain was evaluated at protein concentrations of 100 nM and 500 nM. The assay was conducted both with the protein alone and in the presence of compound T at a concentration of 100 µM. Non-specific signals were corrected by subtracting the signal from a sensor without immobilized biotin. All experiments were performed on an Octet® R8 system, and the resulting data were plotted and fitted using a 2:1 kinetic model in Octet® Analysis Studio (v.12.2.2.26) Docking calculations

[0148] The docking calculations were performed using the AI based DynamicBind code and the structure for the FoxA1 forkhead domain identified by the pdb code 7VOX (https: / / doi.org / 10.1038 / s41467-024-45461-2). All the option has been left at the default value.

[0149] Cell Lines

[0150] LNCaP, 22rv1, PC3, DU145, HS-5, HEK293T and H660 cell lines were purchased from ATCC (American Tissue Culture Collection) (Manassas, USA). The LAPC-4 cell line was a gift from Prof. Helmut Klocker. The supernatant of all cell lines was routinely tested (once per month) using the MycoAlertTM Mycoplasma Detection Kit (Catalog #: LT07-318 Lonza). All cell lines resulted negative for Mycoplasma infection.

[0151] Cell Culture

[0152] The LNCaP, 22rv1, PC3, DU145, MCF-7 cell lines were cultured in RPMI 1640 medium (Cat 21875-24, Gibco) supplemented with 10% Fetal Bovine Serum (FBS-11A Capricorn Scientific) and 1% Penicillin / Streptomycin (15140-122 Life Technologies) with 5% CO2 at37°C. The LAPC-4 cell line was cultured in RPMI 1640 medium (Cat 21875-24, Gibco) supplemented with 10% Fetal Bovine Serum (FBS-11A Capricorn Scientific), 1nM of DHT and 1% Penicillin / Streptomycin (15140-122 Life Technologies) with 5% CO2 at 37°C. The HEK 293T and HS-5 cell lines were cultured in DMEM medium (Cat 2688-133, Gibco) supplemented with 10% FBS and 1% µg / ml Penicillin / Streptomycin with 5% CO2 at 37°C. H660 cells medium was generated accordingly to ATCC protocol in RPMI 1640 medium (Cat 21875-24, Gibco) 0.005 mg / ml Insulin (Thermo Fisher Scientific 12585014), 0.01 mg / ml Transferrin (Merck 10652202001), 30nM Sodium selenite (Sigma 214485-5g), 10 nM Hydrocortisone (StemCell Technology 07925), 10 nM betaestradiol (Sigma E8875-1G), extra 2mM L-glutamine (Gibco 25030149), 5% fetal bovine serum (FBS-11A Capricorn Scientific). MSKPCa-1 organoid cells were grown in Drost medium, freshly renewed every two days.

[0153] Antibodies per Immunoblot and immunoprecipitation

[0154] The primary antibodies used are anti-FOXA1 (E7E8W, CST), anti-FOXA2 (D56D6, CST), anti-GAPDH (0411- Santa Cruz), anti-AR (133273 abeam), anti-NKX2.1 (D2E8, CST), anti-ASCL1 (E7N9C, CST), anti-HSP90 (C45G5, CST), anti-HOXB13 (D7N80, CST), anti-SOX2 (ab79351, Abeam), anti-PSA (D11E1, CST), anti-NKX3.1 (D2Y1A, CST), anti-GATA3 (D13C9, CST), anti-ER (D8H8, CST) anti-VCL (SAB14004522, SIGMA), anti-Alpha Tubulin (DM1A, CST). Snap- frozen cellular pellet was lysed using RIPA Buffer supplemented with a cocktail of phosphatase inhibitors (4906845001 Roche) and protease inhibitors (5892953001 Roche). The protein concentration was determined using a BCA reagent (A52255 Thermo Fisher Scientific). 30-50 pg of whole protein lysate was separated on 8-12% SDS-polyacrylamide gels and transferred onto PVDF membrane (88518 Thermo Fisher Scientific). The membranes were first blocked with 5% milk in Tris Buffered Saline with Tween 20 (TBST) for 30 minutes at room temperature. After that, they were incubated with primary antibodies overnight at 4°C. Then, they were incubated with secondary antibodies (anti-rabbit IgG HRP W401B and anti-mouse IgG HRP W402B Promega) for 1 hour at room temperature. The protein bands were visualized using the western bright quantum reagent (K-12042-D20 Advansta) and quantified using the Fusion Solo IV LBR system.

[0155] LNCaP and PC3 ChlPseq

[0156] 50 million cells were fixed with 1% formaldehyde at room temperature for 10 min and quenched. Nuclear separation was performed using 50 mM Hepes-KOH pH 7.5, 140 mM NaCI, 1 mM EDTA pH 8.0, 10% glycerol, 0.25% Triton X-100 and 0.5% NP40 and protease inhibitor (05892953001, Roche). Nuclei were washed and after lysed in lysis buffer (10 mM Tris HCl pH 8.0, 100 mM NaCI, 1 mM EDTA pH 8.0, 0.5 mM EGTA pH 8.0, 0.1% Na-deoxycholate (freshly made), 0,5% N-lauroylsarcosine Salt and protease inhibitor (05892953001, Roche). Chromatin was sonicated to 200-600 bp using a Bioruptor Plus (BIORUPTOR) (high power, 30 cycles, 30 sec ON 30 sec OFF). Antibodies (FOXA1 ab23738 Abeam; H3K27ac C15410196 Diagenode; FOXA2 D56D6 CST) were incubated with sonicated chromatins overnight. Subsequently 50 µl of Dynabeads protein G (Invitrogen) were added for 5 to 6 hours. Chromatins were washed with NaCI wash buffer (50 mM Hepes pH 7.8, 500 mM NaCI, 1mM EDTA, 1% Triton X 100, 0.1% Na-deoxycholate and protease inhibitor) two times for 10 min sequentially. Chromatins were washed with LiCI wash buffer (20 mM Tris-HCI pH8, 250 mM LiCI, 1mM EDTA, 0.5% NP-40 and protease inhibitor) two times for 10 min sequentially. DNA extraction was performed using QIAquick PCR Purification Kit (Qiagen).

[0157] ChlP-seq data processing and analysis

[0158] ChlP-seq libraries were constructed and next-generation sequencing (100nt, single-end) was performed. Based on the Nextflow nf-core open-source pipeline chipseq version 1.2.2 (doi: 10.5281 / zenodo.3240506, PMID: 32055031) for ChlP-seq peak-calling, QC and differential analysis, FASTQ files were first processed to BAM files using BWA software (PMID: 19451168) and reference Genome assembly GRCh38. From the alignment files peaks calling was performed using MACS2 (PMID: 18798982) software and created corresponding normalized bigWig files scaled to 1 million mapped reads using BEDTools (PMID: 20110278).

[0159] To compare the peak scores between FOXA1 and FOXA2 chip-seqs a merged peak set using BEDTools (PMID: 20110278) merge function was created, and the signal scores for each condition was computed using UCSC tool bigWigAverageOverBed (PMID: 20639541). To compare the peak intensities between different conditions (Eg: DK vs parental or T-compound vs DMSO) computeMatrix tool from python deepTools (PMID: 27079975) was used and the scores were then visualized as heatmaps and density plots using plotHeatmap and plotProfile tools respectively.

[0160] Motif analysis in ChlP-seq peaks

[0161] A list of cell type-specific peak coordinates of FOXA1 and FOXA2 binding regions was generated to identify the transcription factor motifs enriched in those regions. Enrichment of transcription factor motifs under different conditions was analysed using the function findMotifsGenome from HOMER (v5.0.1) (PMID: 20513432). Motif enrichment analyses were centered on the 200 bp surrounding the peak summit. Chi-square statistical test was used to show the significant relative enrichment of transcription factor motifs in T-compound treated cells relative to control treatment.

[0162] In vitro colony forming assay 30 thousand PC3, LNCaP, 22rv1, DU145, LAPC-4, HEK 293T, HS-5 were seeded in each well of a 6-well plate. The day after cells were treated with 10uM, 25uM, 50uM, 75uM, 100uM of compound T. Endpoint was obtained when DMSO treated cells reached a sufficient level of confluence (in a range of 2-4 weeks after the seeding). Before Crystal violet staining, full images of each well were obtained with Incucyte SX3 (Sartorius). After washes and drying of crystal violet, images were taken using Fusion Solo IV LBR system. Finally, crystal violet solution was dissolved using 33% acetic acid and absorbance (595nM) was measured with Cytation 5 Cell Imaging Multi-Mode Reader (BioTek). Antitumor activity of dT3 and dT4 in xenograft experiments

[0163] The animal experiments were carried out in male NRG mice (NOD Rag gamma, 6-8-week-old) accordingly to protocol approved by the Swiss Veterinary Authority (No. TI-58-2024). 2 x 106PC3 cells, 75µl of PBS and Matrigel 1 / 1 and subcutaneously injected into the dorsal flanks of the mice. Tumor growth was recorded using a digital caliper, and tumor volumes were calculated using the formula (Lx W2) / 2, where L = length and W= width of tumor. The vehicle used for dT3 and dT4 administration is corn oil. For vehicle, dT3 (25 mg / kg) and dT4 (25mg / kg) treatment, the mice were grouped randomly, and the treatment started when the mean tumor volume reached 50 mm3. Tumor volume and weight were measured two times per week. Mouse house ambient temperature was between 20 and 22 °C with humidity between 50 and 65% and a dark / light cycle of 12 h each.

[0164] ABBREVIATIONS USED IN THE PRESENT DESCRIPTION FOXA1: Forkhead box protein A1

[0165] FOXA2: Forkhead box protein A2

[0166] ChlPseq: Chromatin Immunopreciptation followed by Sequencing

[0167] SPR: Surface Plasmon Resonance

[0168] DSF: Differential Scanning Fluorimetry

[0169] BLI: Biolayer Interferometry

[0170] ADT: Androgen Deprivation Therapy

[0171] AR: Androgen Receptor

[0172] NEPC: Neuroendocrine Prostate Cancer

[0173] WNT: Wingless and lnt-1

[0174] SCL: Stem-Cell-Like

[0175] AP1: Activator Protein 1

[0176] SOX2: SRY-box transcription factor 2

[0177] NKX2-1: NK2 homeobox 1

[0178] HOXB13: Homeobox protein B13

[0179] ASCL1: Achaete-scute family bHLH transcription factor 1

[0180] IC50: Half-maximal inhibitory concentration

Claims

CLAIMS1. A compound having formula T:Formula Twherein:RI, R2, R3, R4, RS, RS, R?, Rs, R9, Rioare selected independently of each other from:H, OH, CH3, CH2CH3, OCH2CH3, COOH or an amide or an carbonyl group or a sulfamide or a halogen atom selected from: Cl, F, Br, I or an alkyl group selected from: methyl group or ethylmethyl group, isobutyl or tert-butyl,wherein Xi, X2, X3, X4, X5, X6, X7, X8, X9, X are selected independently of each other from O, N, C and S and n is between 0 and 3, for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases.

2. A compound for use according to claim 1, wherein R1, R2, 3 and / or R4 is a COOH or a halogen, R10 and / or Re is COOH, H, a halogen ora carbonyl group.

3. A compound for use according to claim 1 or 2 wherein R5, R7, Rs and / or Rg is H, a halogen, OCH2CH3 or a COOH.

4. A compound for use according to any one of the claims from 1 to 3, wherein R is selected from OH, CH3, CH2CH3, OCH2CH3, COOH, an amide, carbonyl group, a halogen, an alkyl group and Re, R7,, Rs, Rg is H.

5. A compound for use according to any one of the claims from 1 to 4, wherein R1, R2,, R3, R4, R10 and / or Re is COOH and wherein Xi, X2, Xs, X4, X5, X6, X7, X8, X9, X are all C atoms, preferably n is 0.

6. A compound for use according to any one of the claims from 1 to 5, where in:Xi, X2, X3, X4, X5, X6, X7, X8, X9, and X10 is C;R4or Rs is COOH;Ri, R2 and R3is H;Re, R7, R8, R9, and R are selected independently of each other from: H, CH3, or a halogen atom selected from: Cl, F, Br, I7. A compound selected from one of the compounds having the following formula:

8. A compound selected from one of the compounds having the following formula:

9. A compound according to claim 7 or 8, for use in a method of treatment of a cancer or any other FOXA1 / FOXA2-dependent diseases.

10. A compound according to any one of the claims from 1 to 9, for use in combination with hormonal therapy, for example anti-androgen, anti-estorgen therapy or other targeted therapies for example chemotherapy, radiotherapy or immunotherapy.

11. A compound for use according to any one of the claims from 1 to 10, wherein said cancer is selected from breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer and hepatocellular carcinoma.

12. A pharmaceutical composition comprising a compound according to any one of the claims from 1 to 10 for use in a method of treatment of a cancer or any other FOXA1 / FOXA2- dependent diseases, in particular in the treatment of breast cancer, prostate cancer, adenocarcinoma of the stomach, neuroendocrine cancer, lung cancer or hepatocellular carcinoma.

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